WO2003082882A1 - Derive phospholipidique - Google Patents

Derive phospholipidique Download PDF

Info

Publication number
WO2003082882A1
WO2003082882A1 PCT/JP2003/003966 JP0303966W WO03082882A1 WO 2003082882 A1 WO2003082882 A1 WO 2003082882A1 JP 0303966 W JP0303966 W JP 0303966W WO 03082882 A1 WO03082882 A1 WO 03082882A1
Authority
WO
WIPO (PCT)
Prior art keywords
phospholipid
group
compound
phospholipid derivative
drug
Prior art date
Application number
PCT/JP2003/003966
Other languages
English (en)
Japanese (ja)
Inventor
Chika Itoh
Kazuhiro Kubo
Syunsuke Ohhashi
Tohru Yasukohchi
Hiroshi Kikuchi
Norio Suzuki
Miho Kurosawa
Hitoshi Yamauchi
Original Assignee
Nof Corporation
Daiichi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nof Corporation, Daiichi Pharmaceutical Co., Ltd. filed Critical Nof Corporation
Priority to JP2003580347A priority Critical patent/JP4480402B2/ja
Priority to EP03715589.2A priority patent/EP1498420B1/fr
Priority to US10/508,704 priority patent/US7495116B2/en
Priority to AU2003220917A priority patent/AU2003220917A1/en
Publication of WO2003082882A1 publication Critical patent/WO2003082882A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/556—Derivatives containing from 2 to 10 oxyalkylene groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/10—Phosphatides, e.g. lecithin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
    • C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
    • C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
    • C08G65/2609—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aliphatic hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/335—Polymers modified by chemical after-treatment with organic compounds containing phosphorus
    • C08G65/3353—Polymers modified by chemical after-treatment with organic compounds containing phosphorus containing oxygen in addition to phosphorus

Definitions

  • the present invention relates to a phospholipid derivative containing a branched polyalkylene oxide and a method for producing the same.
  • the present invention also relates to a surfactant, a solubilizer, a cosmetic dispersant, and a lipid membrane structure containing the phospholipid derivative.
  • particulate drug carriers such as liposome preparations and polypeptides such as protein preparations have poor retentivity in blood, and cause reticuloendothelial system tissues such as liver and spleen.
  • RES reticuloendothelial system tissues
  • the presence of RES has led to the development of targeted drug carriers, which deliver drugs to organs other than RES, and microparticulate drug carriers as sustained release drugs, which control drug release by retaining the drug in the blood for a long time. This is a major obstacle to its use.
  • glycolipids For example, glycophone (Abstracts of the 106th Annual Meeting of the Pharmaceutical Society of Japan, 336 pages, 1986), ganglioside GM1 (FEBS letter, 223 volumes, 42 pages, 1987), phosphatidylinositol (FEBS letters, 223 volumes, 42 1987), Glycophon and Gandarioside GM 3 (Japanese Patent Application Laid-Open No.
  • two water-soluble polymers are introduced using triazine to reduce the number of bonding points and increase the amount of active groups such as lysine residues in the polypeptide.
  • active groups such as lysine residues in the polypeptide.
  • ribosome preparations there are reports that two water-soluble polymers were introduced into triazine and used to modify the liposome surface in order to increase the molecular weight of the water-soluble polymer. This modification is limited to two. In this case, it is considered that the effect of imparting microcirculation to the liposome surface is smaller than that in the case of having a hydrophilic group.
  • phospholipid derivatives containing polyalkylene oxide groups are also used as surfactants, but none have been known that are highly safe for living organisms and can be used stably under high salt concentration conditions. . Disclosure of the invention
  • An object of the present invention is to provide a novel phospholipid derivative containing a polyalkylene oxide. Is to do. More specifically, the present invention provides a phospholipid derivative which is highly safe for a living body and can be suitably used in the field of solubilization and dispersion of a physiologically active substance or the like, or drug delivery system such as ribosome or cosmetics. It is an object of the present invention to do so.
  • the present inventors have made intensive studies to solve the above problems, and as a result, have succeeded in providing a novel phospholipid derivative represented by the following general formula and a method for producing the same.
  • Z represents a residue of a compound having 3 to 10 hydroxyl groups; AO represents an oxyalkylene group having 2 to 4 carbon atoms; RiCO and R 2 CO independently represent 8 to 22 carbon atoms.
  • X represents a hydrogen atom, an alkali metal atom, an ammonium or an organic ammonium; a represents an integer of 0 to 4; b represents 0 or 1; Q represents a hydrogen atom or a methyl group.
  • m represents the average number of moles of the oxyalkylene group added;
  • m, k1, k2, and k3 represent the following conditions: 3 ⁇ m ⁇ 200, 9 ⁇ mX (k1 + k2 + k 3) ⁇ 1000, 1 ⁇ k 1 ⁇ 2, 0 ⁇ k 2 ⁇ 9, and 0 ⁇ k 3 ⁇ 9 and 3 ⁇ k 1 + k 2 + k 3 ⁇ 10)
  • the present invention provides a phospholipid derivative represented by the formula: +
  • the above 4 kl + k 2 + k 3 ⁇ 8 A phospholipid derivative wherein WCC) and R 2 CO are each independently an acyl group having 12 to 20 carbon atoms; a phospholipid derivative wherein k 2 is 0; There is provided the above phospholipid derivative wherein b is 0; and the above phospholipid derivative wherein k3> 1 and k2> k3.
  • the present invention provides a surfactant comprising a phospholipid derivative represented by the above general formula (1); a solubilizer comprising a phospholipid derivative represented by the above general formula (1)
  • a dispersant containing the phospholipid derivative represented by the general formula (1) preferably a cosmetic dispersant; a lipid membrane structure containing the phospholipid derivative represented by the general formula (1), preferably Is provided with ribosomes.
  • R 1 and R 2 each independently represent a hydrocarbon group having 8 to 22 carbon atoms; R 3 represents a divalent hydrocarbon group having 2 to 4 carbon atoms; X represents a hydrogen atom; A represents an integer of 0 to 4; Y represents a hydrogen atom or N-hydroxysuccinimide.
  • Step A represents a residue of a compound having 3 to 10 hydroxyl groups; AO represents one or more of oxyalkylene groups having 2 to 4 carbon atoms, and two or more oxyalkylenes When it represents a group, it may be in a block form or a random form; m represents the average number of moles of the oxyalkylene group; m and k represent the following conditions: 3 ⁇ m ⁇ 200, 9 ⁇ m X is a number satisfying k ⁇ 1000 and 3 ⁇ k ⁇ 10) in an organic solvent in the presence of a basic catalyst (hereinafter referred to as "Step A”) May be provided.
  • This method can be carried out preferably at a temperature in the range of 20 to 90 ° C., and is preferably carried out in the presence of a dehydrating condensing agent.
  • the present invention provides a method for producing a phospholipid derivative represented by the above general formula (1), which comprises the following general formula (4):
  • Y represents a hydrogen atom or N-hydroxysuccinimide
  • k4 and k5 are as follows: l ⁇ k4 ⁇ 10, 0 ⁇ k5 ⁇ 9, 3 ⁇ k4 + k5 ⁇ 10
  • a method is also provided which comprises a step of reacting a crystalline derivative with an organic solvent in the presence of a basic catalyst. This method can be preferably carried out in the range of 20 to 90 ° C.
  • Z is a residue of a compound having 3 to 10 hydroxyl groups.
  • the type of the compound having 3 to 10 hydroxyl groups is not particularly limited, and examples thereof include glycerin, diglycerin, pentaerythritol, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, and octaglycerin. Of the polyglycerin compounds.
  • the residue of the compound having 3 to 10 hydroxyl groups refers to the total number of branches (k 1 + k 2 + k 3) represented by k 1, k 2, and k 3 from the compound. ) Means the remaining part excluding the hydroxyl group.
  • kl + k2 + k3 corresponds to the number of branches of Z, and is an integer in the range of 3 to 10, preferably 3 to 8, and more preferably 4 to 8.
  • the numerical range indicated by “to” is a range including the upper and lower numerical values). If the number of branches is less than 3, the desired effect of the compound may not be achieved. If the number of branches is greater than 10, the viscosity of a branched material represented by polyglycerin or the like increases, making handling difficult. In some cases, and it may be difficult to obtain raw materials.
  • kl is the number of the partial structure containing the residue of the phospholipid compound represented by the formula (2) bonded to the residue represented by Z, and is 1 or 2.
  • the number of partial structures containing the above phospholipid compound When the number of partial structures containing the above phospholipid compound is 0, it is difficult to stably bind to liposomes or other lipid bilayers due to the absence of a hydrophobic binding portion, making it difficult to modify the liposome membrane. It is. When the number of the partial structures containing the above phospholipid compound is larger than 2, the number of phospholipid residues contained in one molecule is large, and the hydrophobic bond to the liposome membrane is increased. In some cases, the desired effect of the compound of the present invention may not be obtained.
  • R 1 CO and R 2 CO each independently have 8 to 24 carbon atoms, preferably 12 to 20; More preferably, it represents 14 to 18 acyl groups.
  • the type of the acyl group is not particularly limited, and any of an aliphatic acyl group and an aromatic acyl group may be used. Usually, an acyl group derived from a fatty acid can be preferably used.
  • I ⁇ as CO and R 2 CO specific ones for example the force prills acid, force purine acid, lauric acid, myristic acid, Pa palmitic acid, palmitic train acid, stearic acid, isostearic acid, Orein acid, linoleic acid, Examples thereof include an acyl group derived from a saturated or unsaturated linear or branched fatty acid such as araquinic acid, behenic acid, erlic acid, and lignoceric acid.
  • O and R 2 CO may be the same or different. If the number of carbon atoms exceeds 24, the dispersion in the aqueous phase may be poor and the reactivity may decrease.
  • k2 indicates the number of the partial structure represented by one COOX at the terminal bound to the residue represented by Z, and is selected from the range of 0-9. When it is 0, it means that the compound of the present invention has substantially no partial structure represented by COOX at the end.
  • X represents a hydrogen atom, an alkali metal atom, an ammonium, or an organic ammonium, and is preferably a hydrogen atom or an alkali metal atom. Specific examples thereof include sodium and potassium as alkali metal atoms, and triethylammonium as organic ammonium.
  • k3 represents the number of the partial structure having a hydroxyl group or a methyl group at the terminal bonded to the residue represented by Z, and is selected from the range of 0-9.
  • Q is a hydrogen atom or a methyl group.
  • the compound of the present invention may lose its hydrophilicity.
  • b is an integer of 0 or 1
  • a is preferably an integer of 1 to 4, and more preferably a is 2 or 3.
  • a is preferably 1 or 0, and more preferably a is 0.
  • the oxyalkylene group represented by AO is an oxyalkylene group having 2 to 4 carbon atoms, preferably 2 or 3, and examples thereof include an oxyethylene group, an oxypropylene group, an oxytrimethylene group, and an oxybutylene group. . Of these, oxy An ethylene group and an oxypropylene group are preferred, and an oxyethylene group is particularly preferred.
  • the polyoxyalkylene group represented by one (AO) ra — may be composed of only one oxyalkylene group, or may be a combination of two or more oxyalkylene groups. When two or more oxyalkylene groups are combined, the method of combination is not particularly limited, and the polyoxyalkylene group may be block-shaped or random. When the ratio of oxyethylene groups to all oxyalkylene groups is low, the water solubility may decrease, so that the ratio of oxyethylene groups to all oxyalkylene groups is preferably 50 to 100 mol%.
  • m represents an average number of added moles of the oxyalkylene group, and is a number of 3 to 200, preferably 7 to 80. If m is less than 3, the desired effect may be reduced when the phospholipid derivative of the present invention is used in a drug delivery system. On the other hand, when it is larger than 200, the reactivity between the phospholipid compound represented by the formula (2) and the polyalkylene oxide compound represented by the formula (3) during the production of the phospholipid derivative of the present invention. The viscosity may decrease, and the viscosity of the polyalkylene oxide compound represented by the formula (3) may increase and the workability may decrease.
  • m means the number of oxyalkylene groups contained in the polyoxyalkylene groups present in the [kl + k2 + k3] individual branches present in the compound of the present invention.
  • m X [k 1 + k 2 + k 3] means the number of oxyalkylene groups contained in the entire compound of the present invention, and is 9 to 100, preferably 20 to 700, more preferably Is a number from 30 to 350.
  • the method for producing the compound of the present invention represented by the formula (1) is not particularly limited, but a phospholipid derivative in which k 2 is 0 can be produced, for example, in step A with high purity.
  • R R and a are the same as those described in the formula (1), and Y is a hydrogen atom or N-hydroxysuccinimide.
  • the phospholipid compound represented by the formula (2) can be produced by a known method. For example, as described later, it can be easily produced by reacting a phospholipid compound with a dicarboxylic anhydride.
  • the phospholipids used can be natural phospholipids. It may be a synthetic phospholipid, and examples thereof include natural and synthetic phosphatidylethanolamines such as soybean and soybean hydrogenated phosphatidyldiethanolamine, egg yolk and egg yolk hydrogenated phosphatidyldiethanolamine.
  • Z, A O and m are the same as those described in the formula (1). It corresponds to the sum of kl, k2, and k3 described in Equation (1).
  • the reaction between the phospholipid compound represented by the formula (2) and the polyalkylene oxide compound represented by the formula (3) can be carried out in an organic solvent in the presence of a basic catalyst. This can be done using.
  • the type of the basic catalyst is not particularly limited.
  • nitrogen-containing substances include triethylamine, pyridine, dimethylaminopyridine, ammonium acetate, and the like
  • organic salts include sodium phosphate, sodium carbonate, sodium hydrogen carbonate, and boron. Examples thereof include sodium acid and sodium acetate.
  • the amount of the basic catalyst is, for example, 1.5 to 10 times, preferably 2 to 5 times the mole of the polyalkylene oxide compound represented by the formula (2).
  • the organic solvent any solvent having no reactive functional group such as a hydroxyl group can be used without any particular limitation. Examples include ethyl acetate, dichloromethane, chloroform, benzene and toluene. Of these, chloroform and toluene are preferred.
  • An organic solvent having a hydroxyl group such as ethanol may react with a terminal carboxyl group of the polyalkylene oxide compound represented by the formula (2).
  • a dehydrating condensing agent When a dehydrating condensing agent is used, there is no particular limitation as long as the dehydrating condensing agent is capable of dehydrating and condensing the carbonyl group of the polyalkylene oxide compound represented by the formula (3) with the functional group of the phospholipid represented by the formula (2). Can be used. Examples of such a dehydrating condensing agent include carbodiimide derivatives such as dicyclohexylcarbodiimide, and dicyclohexylcarbodiimide is particularly preferred.
  • the amount of the dehydrating condensing agent used is, for example, 1.05 to 5 times, preferably 1.5 to 2.5 times the mol of the polyalkylene oxide compound represented by the formula (3). N-Hydroxysuccinic acid imide In some cases, the yield can be increased by adding 0.1 to 2 times mol of the polyalkylene oxide compound represented by the formula (3) in the reaction system.
  • the reaction temperature of step (A) is usually in the range of 20 to 90 ° C, preferably 40 to 80 ° C.
  • the reaction time is 1 hour or more, preferably 2 to 8 hours.
  • the reaction rate is low, and at a temperature higher than 90 ° C, the acyl group of the phospholipid compound represented by the formula (2) used for the reaction may be hydrolyzed.
  • the compound represented by the formula (1) of the present invention is obtained by reacting an activated ester derivative of a phospholipid compound represented by the formula (2) with a polyalkylene oxide compound represented by the formula (3). Can also be manufactured.
  • the activated ester derivative can be obtained, for example, by reacting a phospholipid compound represented by the formula (2) with an activating agent in the presence of a dehydrating condensing agent.
  • the type of the above-mentioned activator is not particularly limited.
  • ⁇ -hydroxysuccinimide is preferred.
  • the reaction between the phospholipid compound represented by the formula (2) and the activator is carried out in the same manner as the reaction with the dicarboxylic acid anhydride, in the presence of a dehydrating condensing agent and does not react with the carboxylic acid, for example, chloroform, toluene.
  • the reaction can be carried out at a reaction temperature of 15 to 80 ° C., preferably 25 to 55 ° C., for example, by dispersing the activator in a solution of the polyalkylene oxide compound and stirring. Can be performed.
  • N-hydroxysuccinimide when N-hydroxysuccinimide is used as the activator, the carboxyl group of the phospholipid compound represented by the formula (2) reacts with the imide group of N-hydroxysuccinimide, An activated ester derivative in which N-hydroxysuccinimide is bound to the carboxyl group end of the phospholipid compound represented by (2) is obtained.
  • a phospholipid derivative in which k 2 is not 0, that is, a branched oxya Compounds having a partial structure in which the carboxyl group terminal is a carboxyl group are represented by the above general formula
  • the polyalkylene oxide derivative represented by (4) and the phospholipid derivative represented by the above general formula (5) are produced in high purity by reacting in an organic solvent in the presence of a basic catalyst. Can be.
  • the organic solvent used for the reaction can be used without any particular limitation as long as it does not have a reactive functional group such as a hydroxyl group.
  • a reactive functional group such as a hydroxyl group. Examples include ethyl acetate, dichloromethane, chlorophonolem, benzene and toluene. Of these, chlorophonolene and toluene are preferred.
  • An organic solvent having a hydroxyl group, such as ethanol, may react with the terminal hydroxyl group of the polyalkylene oxide compound represented by the formula (4).
  • the type of the basic catalyst used in the reaction is not particularly limited.
  • the nitrogen-containing substance include triethylamine and ammonium acetate
  • the organic salts include sodium phosphate, sodium carbonate, sodium hydrogencarbonate, sodium borate and sodium borate. And sodium acetate.
  • the amount of the basic catalyst is, for example, 1.5 to 10 times, preferably 2 to 7 times the mole of the polyalkylene oxide compound represented by the formula (4).
  • the reaction temperature is usually from 20 to 90 ° C, preferably from 40 to 80 ° C.
  • the reaction time is 1 hour or more, preferably 2 to 8 hours.
  • the reaction rate may be low, and at a temperature higher than 90 ° C, the acyl group of the phospholipid compound represented by the formula (5) used in the reaction may be hydrolyzed.
  • the compound of the present invention may be obtained as a single compound by synthesis, or kl, k2, and k3 may be obtained as different mixtures. Such a mixture is also included in the scope of the present invention.
  • a solubilizing solution, an emulsion and a dispersion can be obtained.
  • the surfactant of the present invention is used as an emulsifier, solubilizer or dispersant
  • the emulsifier, solubilizer or dispersant may use only the surfactant of the present invention. Alternatively, it may contain other known components used for dispersion.
  • Solubilization or dispersion form The method is not limited, and examples thereof include a solution in which a fat-soluble substance or the like is dissolved in a dispersion medium such as water or a buffer, and a dispersion in which a fat-soluble substance or the like is dispersed in a dispersion medium such as water or a buffer.
  • the form of the emulsion or solubilizing solution is not limited, and may be a micelle solution formed by the surfactant of the present invention, that is, a micelle solution containing a fat-soluble substance therein, or a dispersion medium such as water or a buffer solution.
  • a micelle solution formed by the surfactant of the present invention, that is, a micelle solution containing a fat-soluble substance therein, or a dispersion medium such as water or a buffer solution.
  • An emulsion solution in which the dispersed particles of the surfactant and the fat-soluble substance of the present invention are present as colloidal particles or larger particles are exemplified.
  • the micelle solution include those having a dispersed particle diameter of 10 to 300 nm, particularly as a polymer micelle solution.
  • the emulsion solution may be an O / W type in which a fat-soluble substance is blended in an oil phase or a W / OZW type in which a fat-soluble substance is blended in an aqueous phase.
  • the fat-soluble substance which can be solubilized or emulsified is not particularly limited. And the like.
  • the form of use as a dispersant in the field of cosmetics is not particularly limited.For example, a water-soluble substance such as ascorbic acid is retained in the internal aqueous phase of the lipid membrane structure, or a fat-soluble substance such as tocopherol is used as a lipid duplex.
  • the target substance can be more stably dispersed in an aqueous solution.
  • the amount of addition is 0.1 to 20% by weight, preferably 0.5 to 7% by weight, based on the total weight of the substances to be solubilized, dispersed, emulsified, and the like. And more preferably 0.5 to 5% by weight.
  • the compound in which k 2 is 0 in the above general formula (1) can be effectively used as a nonionic surfactant particularly under high salt concentration conditions.
  • polyalkylene oxide-modified phospholipids and the like can be used as a surfactant because they have hydrophilicity derived from an oxyalkylene group and hydrophobicity derived from an acyl group.
  • it is usually oxoa typified by polyalkylene oxide-modified phospholipids.
  • Surfactants with alkylene groups produce turbidity when used under high salt conditions. There is a problem.
  • the compound in which Q is a hydrogen atom in the above general formula (1) is characterized in that it can maintain a high solubilizing ability even in a high salt concentration state, and can be used as a surfactant having excellent salt resistance. Further, it can be used as a surfactant having high compatibility with skin in the field of cosmetics.
  • a compound having k 3 ⁇ 1 and k 2> k 3 that is, a compound having a carboxyl group at the terminal of a branched oxyalkylene group, may be used as a pH-sensitive phospholipid. It can be used as an agent.
  • a cationic substance for example, a cationic physiologically active substance
  • a basic substance for example, coating the surface of fine particles containing a cation or a basic substance with the above compound Thereby, it can be stably dispersed in water. Since the compound of the present invention has a polyanionic group, it can be stably dispersed by ionic bonding.
  • k 3 is preferably less than 1.
  • the compound of the present invention represented by the above general formula (1) can be used as a constituent phospholipid of a lipid membrane structure such as ribosome, emulsion, micelle or the like.
  • a lipid membrane structure such as ribosome, emulsion, micelle or the like.
  • the residence time of a lipid membrane structure, preferably a ribosome, in blood can be increased. This effect can be achieved by adding a small amount of the compound of the present invention to the lipid membrane structure.
  • the use of the compound of the present invention having three or more hyperbranches as a constituent phospholipid of the lipid membrane structure allows the polyoxyethylene chain to form the membrane of the lipid membrane structure.
  • the compounding amount of the compound of the present invention in the lipid membrane structure can improve the efficacy of a drug in vivo. It is sufficient that the amount is sufficient for expression, and there is no particular limitation. For example, it can be appropriately selected according to the type of the drug to be retained in the lipid membrane structure, the use for treatment or prevention, the form of the lipid membrane structure, and the like.
  • the type of drug held by the lipid membrane structure provided by the present invention is not particularly limited, but for example, a compound used as an antitumor agent is preferable.
  • These compounds include, for example, irinotecan hydrochloride, nogitecan hydrochloride, exatecan, RFS-2000, Lu rtotecan, BNP-1350, Bay-383441, PNU-166148, I DEC_132, BN-80915, DB_38, DB-81, DB — 90, DB_91, CKD-620, T-1128, ST-1480, ST-1481, DRF-1042, DE-310 and other camptothecin derivatives, docetaxel hydrate, and the like.
  • Taxane derivatives such as clitaxel, IND-5109, BMS-184476, BMS-188797, T-3782, TAX-1011, SB-RA-31012, SBT-1514, DJ-927, diphosphamide, dimustine hydrochloride, carbocon , Cyclophosphamide, dacarbazine, thiotepa, busulfan, me / refharan, lanmustine, estramustine sodium phosphate, 61-mercaptopurine liposide, enositabine, gemcitabine hydrochloride, carmofur, cytarabine, cytarabine otafos de doxate, tigafulin , Hydroxycarbamide, Fluorouracil, Methotrexate, Mercaptopurine, Fludarabine phosphate, Actinomycin D, Aclarubicin hydrochloride, Idarubicin hydrochloride, Evirubicin hydrochlor
  • the lipid membrane structure of the present invention may include a gene or the like.
  • the gene may be any of oligonucleotide, DNA and RNA, and particularly a gene for in vitro transfection or a gene that acts upon expression in in vitro, such as a gene for gene therapy.
  • genes used for breeding industrial animals such as experimental animals and livestock.
  • Examples of the gene for gene therapy include a gene encoding a physiologically active substance such as an antisense oligonucleotide, an antisense DNA, an antisense RNA, an enzyme, and a cytokin.
  • the lipid membrane structure further includes sterols such as phospholipids, cholesterol monoles, cholestano monoles, and other saturated and unsaturated acyl groups having 8 to 22 carbon atoms.
  • sterols such as phospholipids, cholesterol monoles, cholestano monoles, and other saturated and unsaturated acyl groups having 8 to 22 carbon atoms.
  • an antioxidant such as ⁇ -tocopherol.
  • Phospholipids include phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidinoregylglycerolene, cardiolipin, sphingomyelin, ceramidophosphorinoleetanolenoamine, ceramidophosphorylglycerol, ceramidophosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphorylphosphoryl
  • the fatty acid residues of these phospholipids are not particularly limited, but include, for example, saturated or unsaturated fatty acid residues having 12 to 20 carbon atoms.
  • lauric acid, myristic acid examples include an acyl group derived from a fatty acid such as palmitic acid, stearic acid, oleic acid, and linoleic acid.
  • phospholipids derived from natural products such as egg yolk lecithin and soybean lecithin can also be used.
  • the form of the lipid membrane structure containing the compound of the present invention and the production method thereof are not particularly limited.
  • examples of the existing form include a dried lipid mixture form, a form dispersed in an aqueous solvent, a dried form thereof, a frozen form thereof, and the like.
  • a dried lipid mixture for example, it must be prepared by dissolving the lipid components to be used in an organic solvent such as chloroform, and then drying under reduced pressure using an evaporator or spray drying using a spray dryer. Can be.
  • Examples of the form in which the lipid membrane structure is dispersed in an aqueous solvent include monolamellar ribosomes, multilayer ribosomes, w-emulsions, w / oZw-emulsions, spherical micelles, string micelles, and irregular layered structures. Among them, ribosomes are preferred.
  • the size of the dispersed lipid membrane structure is not particularly limited.For example, in the case of liposome-emulsion, the particle size is 50 nm to 5 m, and in the case of spherical micelles, the particle size is 5 nm. From 100 nm. In the case of string-like micelles or irregular layered structures, the thickness of each layer can be considered to be 5 to 10 nm and these layers are formed.
  • the composition of the aqueous solvent is not particularly limited, and examples thereof include buffers such as phosphate buffer, citrate buffer, and phosphate buffered saline, physiological saline, and a medium for cell culture. You may.
  • buffers such as phosphate buffer, citrate buffer, and phosphate buffered saline, physiological saline, and a medium for cell culture. You may.
  • the compound of the present invention is used in an aqueous solvent, the lipid membrane structure can be stably dispersed, but in addition to water, an aqueous sugar solution such as glucose, lactose, and sucrose, glycerin, propylene glycol, and the like can be used.
  • a polyhydric alcohol aqueous solution or the like may be added.
  • the electrolyte in the aqueous solvent from the viewpoint of physical stability such as aggregation.
  • the pH of the aqueous solvent from weakly acidic to near neutral (pH 3.0 to 8.0), and to remove dissolved oxygen by nitrogen bubbling. desirable.
  • an effective storage is possible by using an aqueous sugar solution and an aqueous polyhydric alcohol solution, respectively.
  • the concentration of these aqueous solvents is not particularly limited.
  • the concentration is preferably 2 to 20% (W / V), and more preferably 5 to 10% (W / V). .
  • the content is preferably 1 to 5% (W / V), and more preferably 2 to 2.5% (W / V).
  • the concentration of the buffer is preferably 5 to 5 OmM, more preferably 10 to 2 OmM.
  • the concentration of the lipid membrane structure in the aqueous solvent is not particularly limited, but the concentration of the total lipid in the lipid membrane structure is preferably from 0.1 mM to 50 OmM, more preferably from 1 mM to 10 OmM. .
  • the form in which the lipid membrane structure is dispersed in an aqueous solvent is manufactured by adding the above-mentioned dried lipid mixture to the aqueous solvent, and further emulsifying the mixture with an emulsifier such as a homogenizer, an ultrasonic emulsifier, a high-pressure jet emulsifier, or the like.
  • an emulsifier such as a homogenizer, an ultrasonic emulsifier, a high-pressure jet emulsifier, or the like.
  • the ribosome can be produced by a well-known method, for example, a reverse phase evaporation method, and the method is not particularly limited.
  • extrusion extrusion (extrusion filtration) may be performed under high pressure using a membrane filter having a uniform pore diameter.
  • Examples of the method for further drying the lipid membrane structure dispersed in the aqueous solvent include usual freeze-drying and spray-drying.
  • an aqueous saccharide solution preferably an aqueous sucrose solution and an aqueous lactose solution may be used as described above.
  • the lipid membrane structure can be stored for a long period of time.
  • efficiency can be improved. Since the lipid mixture is well hydrated, there is an advantage that the drug can be efficiently held in the lipid membrane structure.
  • a pharmaceutical composition can be produced by adding a drug to the lipid membrane structure, and the lipid membrane structure can be used as a pharmaceutical composition for treating and / or preventing a disease.
  • the drug is a gene, it can be used as a gene transfer kit.
  • the form of the pharmaceutical composition may be a form in which the lipid membrane structure and the medicine are mixed, or a form in which the medicine is held in the lipid membrane structure.
  • retention means that the drug is present in the membrane of the lipid membrane structure, on the surface, inside, in the lipid layer, and on the surface of the lipid or lipid layer.
  • the existence form of the pharmaceutical composition and the method for producing the same are not particularly limited as in the case of the lipid membrane structure.
  • the form includes a form dispersed in an aqueous solvent, a dried form and a frozen form.
  • the mixed dried product of lipids and medicine is prepared by, for example, dissolving the lipid components to be used and the medicine in an organic solvent such as chloroform, and then drying the mixture under reduced pressure using an evaporator and drying using a spray dryer.
  • an organic solvent such as chloroform
  • Examples of the form in which the mixture of the lipid membrane structure and the drug are dispersed in an aqueous solvent include multilayer liposomes, monolayer ribosomes, o / w type emulsions, wZo / w type emulsions, spherical micelles, string micelles, Examples include an amorphous layered structure, but there is no particular limitation.
  • the size (particle size) of the mixture and the composition of the aqueous solvent are not particularly limited. For example, 50 nm to 2 ⁇ m for ribosomes and 5 to 100 nm for spherical micelles 5 0 ⁇ ⁇ when forming emulsions! ⁇ 5 ⁇ .
  • the concentration in the aqueous solvent as a mixture is not particularly limited. There are several known methods for producing a mixture of a lipid membrane structure and a drug in an aqueous solvent, and the method generally depends on the mode of existence of the mixture of the lipid membrane structure and the drug. It is necessary to select an appropriate manufacturing method as described below. Manufacturing method 1
  • This method involves dissolving the lipid components once in an organic solvent and then emulsifying the dried product from which the organic solvent has been distilled off by adding an aqueous solvent containing a drug to the dried product. If you want to control the size (particle size), you can use a membrane filter with a uniform pore size to perform extrusion under high pressure. It is difficult to dissolve in organic solvents, but can be applied to drugs that dissolve in aqueous solvents. When the lipid membrane structure is a ribosome, there is an advantage that the drug can be retained in the inner aqueous phase. Manufacturing method 3
  • a lipid membrane structure such as ribosome, emulsion, micelle, or layered structure already dispersed in the aqueous solvent.
  • the application of this method is limited to water-soluble medicaments. Since this is a method of adding a drug from the outside to a lipid membrane structure that has already been completed, if the drug is a polymer, the drug cannot enter the inside of the lipid membrane structure and the surface of the lipid membrane structure May take the form of existence linked to When ribosome is used as the lipid membrane structure, using this production method 3, a drug takes a sandwich structure (generally called a complex or complex) sandwiched between ribosome particles. It is known.
  • the drug is limited to a water-soluble one as in Production method 3.
  • the major difference from Production Method 3 lies in the mode of existence of the lipid membrane structure and the drug. That is, in this production method 4, a dried product is produced by temporarily producing a lipid membrane structure dispersed in an aqueous solvent and then drying it. At this stage, the lipid membrane structure exists in a solid state as a fragment of the lipid membrane for fabrication.
  • an aqueous saccharide solution preferably, an aqueous solution of bran or lactose
  • the lipid membrane fragments that existed in the solid state immediately begin to hydrate with the intrusion of water, and the lipid membrane structure can be reconstituted. At this time, a structure in which the drug is held inside the lipid membrane structure can be produced.
  • the production method 3 when the drug is a polymer, the drug cannot enter the lipid membrane structure and takes a mode of being bonded to the surface of the lipid membrane structure, but the production method 4 is large in this point. Is different.
  • this production method 4 since the aqueous dispersion of the lipid membrane structure alone is produced in advance, there is no need to consider the decomposition of the drug during emulsification, and the size (particle size) can be easily controlled. It is relatively easy to manufacture compared to Method 1 and Manufacturing Method 2. In addition, since freeze-drying or spray-drying is performed, it is easy to ensure the storage stability of the preparation, and the size (particle size) can be restored even if the dried preparation is rehydrated with an aqueous pharmaceutical solution. The advantages are that, even in the case of a high molecular drug, the drug can be easily held inside the lipid membrane structure.
  • a well-known method for producing ribosomes for example, a reverse-phase evaporation method or the like may be used separately. If you want to control the size (particle size), use a membrane filter with a more uniform pore size and perform the extrusion under high pressure. Further, as a method for further drying the dispersion in which the mixture of the lipid membrane structure and the drug is dispersed in an aqueous solvent, freeze-drying and spray-drying can be mentioned.
  • an aqueous saccharide solution preferably an aqueous sucrose solution or an aqueous lactose solution
  • a normal freezing method can be used.
  • an aqueous saccharide solution or an aqueous polyhydric alcohol solution may be used.
  • the lipid that can be incorporated in the pharmaceutical composition may be appropriately selected depending on the type of the drug to be used and the like. For example, when the drug is not a gene, 0.1 to 100 parts by weight of the drug is used.
  • the medicament is a gene may be a pharmaceutical (genes) 1 / zg, 5 0 0 nmo 1 is preferably from 1, preferably more 1 0 2 0 0 nmo 1 p
  • the method of using the compound and the pharmaceutical composition of the present invention may be appropriately determined according to the form of use.
  • Means of administration to humans and the like is not particularly limited, and may be oral administration or parenteral administration.
  • Oral dosage forms include, for example, tablets, powders, granules, syrups, capsules, and oral liquids.
  • Parenteral dosage forms include, for example, injections, drops, Examples include eye drops, ointments, suppositories, suspensions, cataplasms, lotions, azones, plasters and the like.
  • injections and infusions are preferred among these, and administration methods include intravenous injection, subcutaneous injection, intradermal injection, and local injection into target cells or organs. .
  • the forms of cosmetics include lotions, creams, lotions, emulsions, foams, foundations, lipsticks, packs, skin cleansers, shampoos, rinses, and conditioners. , Hair tonic, hair liquid, hair cream and the like.
  • the means for administering the medicament and the composition is not particularly limited, and may be oral administration or parenteral administration, but parenteral administration is preferred.
  • the form of the pharmaceutical composition is not particularly limited.
  • Examples of the dosage form for oral administration include tablets, powders, granules, and syrups.
  • Examples of the dosage form for parenteral administration include: Examples include injections, drops, eye drops, ointments, suppositories and the like. Of these, injections and infusions are preferred, and the administration method is preferably intravenous injection or local injection into target cells or organs.
  • Polyoxyethylene penta-risthritol ether (average molecular weight 2000) —Synthesis of monodistearoylphosphadylethanolamine succinate Preparation of distearoylphosphatidylethanolamine succinate
  • the progress of the reaction and identification of products were performed by thin-layer chromatography (TLC) using a silica gel plate.
  • the developing solvent used was a mixed solvent of chloroform and methanol at a mixing ratio of 85:15 by volume.
  • the color was developed with iodine vapor and the content of the substance was determined by comparison with a known amount of a standard substance.
  • a spot of polyoxyethylene pentaerythritol ether average molecular weight: 2000
  • RfO by binding of the phospholipid compound. Confirmation was carried out by converting to a spot detected in the vicinity of 4-0.5.
  • Distearoyl phosphatidylethanolamine succinate obtained in the same manner as in Synthesis Example 1 was dissolved in 1 mL of chloroform and added with triethylamine l O Omg (1 mmo 1). 1.1 g of ethylenehexaglycerol ethereal monodistearoylphosphadylethanolanolamine succinate was obtained.
  • the progress of the reaction and identification of the product were performed by thin-layer chromatography (TLC) as in Synthesis 1.
  • TLC thin-layer chromatography
  • the end point of the reaction is polyoxyethylene hexaglycerol ether (average molecular weight of 20), which is detected near the Rf value of 0.6 to 0.7 by the following TLC.
  • the progress of the reaction and identification of the product were performed by thin-layer chromatography (TLC) as in Synthesis 1.
  • TLC thin-layer chromatography
  • a spot of polyoxyethylene glycerol ether (average molecular weight: 2000), which is detected near the Rf value of 0.6 to 0.7 by the following TLC, has an Rf of 0.4 due to the binding of the phospholipid compound. This was confirmed by conversion to a spot detected at around 0.5.
  • the confirmation of the product was confirmed by the fact that the peak of the amino group (3000 cm " 1 ) in phosphatidylethanolamine was changed to a carbonyl group (1700 cm- 1 ) peak by amide bond in the IR spectrum.
  • the filtrate was removed by suction filtration, and 1 OmL of hexane was added to the obtained filtrate, and the mixture was cooled to 15 ° C or less to precipitate crystals. These crystals were obtained by filtration. To the obtained crystals, 30 mL of ethyl acetate was added and dissolved by heating to 50 ° C, and then cooled to 15 ° C or lower to precipitate crystals. The crystals were collected by filtration. If there were any insolubles during the heating and dissolution, they were removed by filtration and the process proceeded to the next step.
  • the polyoxyethylene pentaerythritol ether used as a raw material had a hydroxyl value of 45 mgKOH / g, and was determined by gel permeation chromatography (GPC) to be polyoxyethylene pentaerythritol ether (molecular weight 5000). Based on the molecular weight of succinimidyl glutarate being 5812, it was confirmed to be a four-branched polyoxyethylene having a molecular weight of about 5,000.
  • the GPC is equipped with SHODEX GPC SYSTEM-11 as a system, SHODEX RI-71 as a differential refractometer, and 4 4L SHODEX KF 804 as a column, column temperature 40 ° C, and tetrahydrofuran as a developing solvent.
  • the sample was flowed at a flow rate of 1 / min, 0.1 ml of a 0.1% by weight tetrahydrofuran solution of the obtained sample was injected, and the molecular weight was calculated using a BORWI NGPC calculation program.
  • Ethyl acetate (3 OmL) was added to the obtained crystals, and the mixture was heated to 50 ° C to dissolve, and then cooled to 15 ° C or lower to precipitate crystals. The crystals were collected by filtration. If there was any insoluble matter during the heating and dissolution, it was removed by filtration and the process proceeded to the next step. The obtained crystals were again dissolved in 2 OmL of ethyl acetate under heating, and 1 OmL of hexane was added. The precipitated crystals were filtered to obtain 5 g of crystals having a final purity of 98%, and the yield was 9%. It was 5%.
  • the hydroxyl value of the polyoxyethylene pentaerythritol ether used as the raw material was 26.7 mg KOH / g, and polyoxyethylene pentaerythritol ether (molecular weight 2000) was determined by gel permeation chromatography (GPC). Based on the molecular weight of succinimidyl succinate being 2082, it was confirmed that it was a four-branched polyoxyethylene having a molecular weight of about 2,000.
  • GPC has the SHODEX GPC SYSTEM-11, SHOD EX RI-71 as a differential refractometer, three SHODEX KF 804 L columns as columns, and a flow rate of 40 CC, tetrahydrofuran as a developing solvent at a flow rate of lm 1 / min. 0.1 lm 1 of a 0.1% by weight tetrahydrofuran solution was injected, and the molecular weight was calculated using a BORWI NGPC calculation program.
  • Example 1 Preparation of lotion (Evaluation as solubilizer)
  • a lotion was prepared using the polyoxyethylene pentaerythritol ether (molecular weight: 5,000) glutaryl-monodistearoylphosphatidylethanolamine of Synthesis Example 5. That is, glycerin and propylene glycol were added to purified water of the base material having the composition shown in Table 1 and uniformly dissolved. The other base material was added to ethanol to make it uniform, and then added to the purified aqueous phase while stirring to solubilize it to obtain a lotion.
  • the oil phase portion containing the emulsifier of the base material having the composition shown in Table 2 was heated to 60 ° C and uniformly dissolved, and then the aqueous phase portion was added at the same temperature while stirring, and the ribosome was added. An emulsion was obtained.
  • Liposomal solution 10.0 w t%
  • the product was analyzed by thin-layer chromatography (TLC) using a silica gel plate.
  • TLC thin-layer chromatography
  • a developing solvent use a mixed solvent of chloroform and methanol in a mixing ratio of 85:15 by weight, develop the color with iodine vapor, and compare the amount with a standard amount of a known amount to determine the qualitative determination of the contained material. went.
  • Example 3 Measurement of Salt Resistance Effect (Evaluation as Surfactant)
  • Example 4 Evaluation as resident ribosome in blood
  • Lipids having the membrane composition ratios shown in Table 1 were weighed, dissolved in a mixture of black-mouth form and methanol (2: 1), and then evaporated with an evaporator. The organic solvent was distilled off, and the residue was further dried under reduced pressure for 1 hour. Next, to the dried lipid (lipid film) was added 1 Om1 of a 55 mM ammonium sulfate aqueous solution (pH 5.5) preheated to 65 ° C. And gently stirred (until the lipids came off the eggplant flask).
  • This lipid dispersion was transferred to a homogenizer, homogenized for 10 strokes, and then sized using polycarbonate membrane filters of various pore sizes (0.2 / imX 3 times, 0.1 / xmX 3 times, 0.05 ⁇ mX 3 times, and 0 ⁇ 5 ⁇ mX 3 times). 03 ⁇ ⁇ 3 times) to prepare an empty ribosome dispersion having a particle diameter of about 100 nm.
  • the empty ribosome dispersion liquid (total lipid concentration 50 mM) and doxorubicin solution (drug concentration: 3.3 mg / m 1 physiological saline) in which the above outer aqueous phase was replaced with physiological saline were previously heated to 60 ° C.
  • the doxorubicin solution 6 was added to the empty ribosome dispersion 4 in a volume ratio (ie, the final drug concentration was 2.0 mg / ml and the final lipid concentration was 20 mM), the mixture was incubated at 60 ° C for 1 hour. Next, this was cooled at room temperature to obtain a doxorubicin-containing ribosome dispersion.
  • each ribosome was around 100 nm.
  • HSPC hydrogenated soy phosphatidylcholine
  • HSPC hydrogenated soy phosphatidylcholine
  • HSPC hydrogenated soy phosphatidylcholine
  • HSPC hydrogenated soy phosphatidylcholine
  • i3 ⁇ 4HSPC hydrogenated soy phosphatidylcholine
  • i3 ⁇ 4DSPE Distearoynophosphatidinorecholine
  • HSPC hydrogenated soy phosphatidylcholine: industrial applicability
  • the phospholipid derivative of the present invention is highly safe for living organisms and is useful as a surfactant, solubilizer, or dispersant in the field of cosmetics and the like.
  • the phospholipid derivative of the present invention which is a hyperbranched polyoxyethylene derivative
  • lipid membrane structures such as ribosomes
  • aggregation of fine particles in an aqueous medium can be achieved without destabilizing the lipid membrane structures.
  • a stable solution state can be obtained.
  • the ribosome containing the phospholipid derivative of the present invention is characterized by having excellent retention in blood.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Birds (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Polymers & Plastics (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biochemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un dérivé phospholipidique sans aucun danger pour le corps vivant, et convenant particulièrement pour la solubilisation ou la dispersion d'une substance physiologiquement active, mais également pour les systèmes de transport de principes actifs tels que les liposomes, mais également pour les cosmétiques. Ce dérivé phospholipidique est représenté par la formule générale (I). Dans cette formule, Z est un groupe restant d'un composé portant de 3 à 10 groupes hydroxy. AO est C2-C4 oxyalkylène. R1CO et R2CO sont chacun C8-C22 acyle. X est hydrogène, métal alcalin, ammonium, or un ammonium organique. Le 'a' est un entier de 0 à 4. Le 'b' vaut 0 ou 1. Q est hydrogène ou méthyle. Le 'm' correspond au nombre moyen de moles de l'oxyalkylène d'adjonction. Enfin, m, k1, k2, et k3 sont des nombres vérifiant les équations suivantes: 3≤m≤200, 9≤m×(k1+k2+k3)≤1000, 1≤k1≤2, 0≤k2≤9, 0≤k3≤9, et 3≤k1+k2+k3≤10.
PCT/JP2003/003966 2002-03-29 2003-03-28 Derive phospholipidique WO2003082882A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2003580347A JP4480402B2 (ja) 2002-03-29 2003-03-28 リン脂質誘導体
EP03715589.2A EP1498420B1 (fr) 2002-03-29 2003-03-28 Derive phospholipidique
US10/508,704 US7495116B2 (en) 2002-03-29 2003-03-28 Phospholipid derivative
AU2003220917A AU2003220917A1 (en) 2002-03-29 2003-03-28 Phospholipid derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002093694 2002-03-29
JP2002-93694 2002-03-29

Publications (1)

Publication Number Publication Date
WO2003082882A1 true WO2003082882A1 (fr) 2003-10-09

Family

ID=28671762

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2003/003966 WO2003082882A1 (fr) 2002-03-29 2003-03-28 Derive phospholipidique

Country Status (5)

Country Link
US (1) US7495116B2 (fr)
EP (1) EP1498420B1 (fr)
JP (1) JP4480402B2 (fr)
AU (1) AU2003220917A1 (fr)
WO (1) WO2003082882A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1591447A1 (fr) * 2003-01-06 2005-11-02 Nof Corporation Derives de phospholipides et procedes de leur production
JP2008516056A (ja) * 2004-10-08 2008-05-15 アルザ コーポレイション リポポリマーコンジュゲート
US7399877B2 (en) 2003-03-20 2008-07-15 Nof Corporation Phospholipid derivative
US7531604B2 (en) 2002-09-30 2009-05-12 Nof Corporation Phospholipid derivative
WO2011059073A1 (fr) * 2009-11-13 2011-05-19 日油株式会社 Dérivé de phospholipide et liposomes réactifs au ph
JP2013529237A (ja) * 2010-05-20 2013-07-18 ビーエーエスエフ ソシエタス・ヨーロピア トリス（２−ヒドロキシフェニル）メタン誘導体並びにその製造及び使用法
JP2014189559A (ja) * 2013-03-26 2014-10-06 Nof Corp 生分解性ポリオキシエチレン誘導体の製造方法

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040062748A1 (en) * 2002-09-30 2004-04-01 Mountain View Pharmaceuticals, Inc. Polymer conjugates with decreased antigenicity, methods of preparation and uses thereof
WO2006023444A2 (fr) 2004-08-17 2006-03-02 Tyco Healthcare Group, Lp Barriere anti-adhesion
CH715456B1 (de) 2007-04-27 2020-04-30 Mibelle Ag Kosmetisches Produkt zur topischen Anwendung für den Schutz und die Erneuerung von Hautstammzellen, welches sich von dedifferenzierten Pflanzenzellen ableitet.
US7666973B2 (en) 2007-07-30 2010-02-23 Tyco Healthcare Group Lp Carbonate copolymers
US20090048423A1 (en) * 2007-08-15 2009-02-19 Tyco Healthcare Group Lp Phospholipid Copolymers
US8268958B2 (en) 2007-08-15 2012-09-18 Tyco Healthcare Group Ip Phospholipid copolymers
CN103881084B (zh) * 2014-03-14 2016-09-28 厦门赛诺邦格生物科技股份有限公司 一种支化聚乙二醇的磷脂类衍生物及其组成的脂质膜结构体

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06228012A (ja) * 1993-01-29 1994-08-16 Dai Ichi Seiyaku Co Ltd リポソーム製剤

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US210618A (en) * 1878-12-10 Improvement in rod-adjusters for oil-wells
US31481A (en) * 1861-02-19 Sewing-work holder
US144247A (en) * 1873-11-04 Improvement in cultivating-plows
US110436A (en) * 1870-12-27 Improvement in tidal motive-powers
US5173219A (en) * 1986-02-12 1992-12-22 Research Development Foundation Uniform spherical multilamellar liposomes of defined and adjustable size distribution
JPH0651109B2 (ja) 1987-03-09 1994-07-06 第一製薬株式会社 脂質膜構造体
JP2676854B2 (ja) * 1988-12-16 1997-11-17 日本油脂株式会社 ポリオキシアルキレン不飽和エーテルーマレイン酸エステル共重合体およびその用途
US5395619A (en) * 1993-03-03 1995-03-07 Liposome Technology, Inc. Lipid-polymer conjugates and liposomes
CA2137297C (fr) 1993-12-06 2000-04-18 Tsuyoshi Miyazaki Vesicule reactive et vesicule fonctionnelle fixee a une substance
JP3620059B2 (ja) 1994-03-04 2005-02-16 日本油脂株式会社 反応性小胞体、形成剤および機能性物質固定化小胞体
JP3480033B2 (ja) 1994-03-31 2003-12-15 日本油脂株式会社 ホスホリルコリン基又はその誘導体基含有共重合体、その製造法及び抗血栓性材料
JPH09255740A (ja) 1996-03-26 1997-09-30 Nof Corp 三元共重合体
DE59805997D1 (de) * 1997-08-18 2002-11-21 Max Planck Gesellschaft Phospholipidanaloge verbindungen
GB9717905D0 (en) 1997-08-22 1997-10-29 Univ Aston Lipid-containing compositions and uses thereof
DE19835611A1 (de) 1998-08-06 2000-02-10 Max Planck Gesellschaft Neuartige Phospholipide mit synthetischen, ungesättigten Alkyl- und Acylketten
AU1787800A (en) 1998-12-08 2000-06-26 Phares Pharmaceutical Research N.V. Phospholipid compositions
EP1202714A1 (fr) 1999-07-16 2002-05-08 Purdue Research Foundation Lipides d'ether vinyliques avec des groupes de tetes hydrophiles clivables
EP1279406A4 (fr) 2000-04-03 2007-10-24 Santen Pharmaceutical Co Ltd Transporteurs et systeme de distribution de medicament les utilisant
DE60208454T2 (de) * 2001-03-02 2006-09-07 Nof Corp. Polyalkylenoxid-modifizierte Phospholipide und Verfahren zu ihrer Herstellung
AU2003266714A1 (en) 2002-09-30 2004-04-19 Daiichi Pharmaceutical Co., Ltd. Phospholipid derivative
CN100339382C (zh) 2003-01-06 2007-09-26 日本油脂株式会社 磷脂质衍生物及其制造方法
JP4526479B2 (ja) 2003-03-20 2010-08-18 日油株式会社 リン脂質誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06228012A (ja) * 1993-01-29 1994-08-16 Dai Ichi Seiyaku Co Ltd リポソーム製剤

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALLEN T.M. ET AL.: "Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1061, no. 1, 1991, pages 56 - 64, XP002970469 *
REINER ZEISIG ET AL.: "Effect of sterical stabilization on macrophage uptake in vitro and thickness of the fixed aqueous layer of liposomes made from alkylphosphocholines", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1285, no. 2, 1996, pages 237 - 245, XP002970468 *
See also references of EP1498420A4 *
TSUTOMU YUDA ET AL.: "Prolongation of liposome circulation time by various derivatives of polyethyleneglycols", BIOLOGICAL & PHARMACEUTICAL BULLETIN, vol. 19, no. 10, 1996, pages 1347 - 1351, XP000633464 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7531604B2 (en) 2002-09-30 2009-05-12 Nof Corporation Phospholipid derivative
EP1591447A1 (fr) * 2003-01-06 2005-11-02 Nof Corporation Derives de phospholipides et procedes de leur production
US7524981B2 (en) 2003-01-06 2009-04-28 Nof Corporation Phospholipid derivatives and process for the production there
EP1591447A4 (fr) * 2003-01-06 2009-11-11 Nof Corp Derives de phospholipides et procedes de leur production
US7399877B2 (en) 2003-03-20 2008-07-15 Nof Corporation Phospholipid derivative
JP2008516056A (ja) * 2004-10-08 2008-05-15 アルザ コーポレイション リポポリマーコンジュゲート
WO2011059073A1 (fr) * 2009-11-13 2011-05-19 日油株式会社 Dérivé de phospholipide et liposomes réactifs au ph
US8445712B2 (en) 2009-11-13 2013-05-21 Nof Corporation Phospholipid derivative and pH-responsive liposomes
JP2013529237A (ja) * 2010-05-20 2013-07-18 ビーエーエスエフ ソシエタス・ヨーロピア トリス（２−ヒドロキシフェニル）メタン誘導体並びにその製造及び使用法
JP2014189559A (ja) * 2013-03-26 2014-10-06 Nof Corp 生分解性ポリオキシエチレン誘導体の製造方法

Also Published As

Publication number Publication date
JPWO2003082882A1 (ja) 2005-08-04
EP1498420A1 (fr) 2005-01-19
US20050220856A1 (en) 2005-10-06
JP4480402B2 (ja) 2010-06-16
EP1498420A4 (fr) 2010-12-08
EP1498420B1 (fr) 2017-02-01
AU2003220917A1 (en) 2003-10-13
US7495116B2 (en) 2009-02-24

Similar Documents

Publication Publication Date Title
WO2003082882A1 (fr) Derive phospholipidique
EP0657463A1 (fr) Dérivés de phospholipides et vésicule les contenant
CZ2002140A3 (cs) Neutrální lipopolymer a lipozomové kompozice, které jej obsahují
EP1241172B1 (fr) Derivés de phospholipides à chaîne oxyde de polyalkylene et leur methode de preparation
JP4540287B2 (ja) ポリアルキレンオキシド修飾リン脂質の製造方法
JP5515360B2 (ja) 脂質誘導体
JP2019151589A (ja) 脂質ナノ粒子
JP4710109B2 (ja) ポリアルキレンオキシド修飾リン脂質、その製造方法および用途
JP4403303B2 (ja) リン脂質誘導体及びその製造方法
JP4808403B2 (ja) リン脂質誘導体
JP4526479B2 (ja) リン脂質誘導体
KR20200025180A (ko) 향상된 흡수력을 갖는 경피 흡수 마이셀 및 이를 포함하는 경피 흡수 조성물
JPH07165770A (ja) リン脂質誘導体
EP4368657A1 (fr) Dérivé lipidique sensible au ph
CN117534585A (zh) 一种新型可电离阳离子脂质化合物及其制备方法与应用
JPH092975A (ja) 反応性小胞体形成剤および反応性小胞体
JPH07165771A (ja) 反応性小胞体および形成剤
JPH07242681A (ja) リン脂質誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003580347

Country of ref document: JP

REEP Request for entry into the european phase

Ref document number: 2003715589

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2003715589

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2003715589

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10508704

Country of ref document: US